We have previously demonstrated that iloprost, a stable prostacyclin (PGI2) analogue, induces angiogenesis in vivo, through a vascular endothelial growth factor (VEGF)-dependent mechanism. In this study, we demonstrate that iloprost-induced angiogenesis and VEGF upregulation are modulated by peroxisome proliferator-activated receptor-α (PPARα), a ligand-inducible transcription factor that belongs to the nuclear hormone receptor superfamily and plays multiple biological activities in the vascular system. We show that iloprost is unable to induce angiogenesis in mice lacking the PPARα gene (PPARα–/– mice). Likewise, iloprost-induced VEGF upregulation is absent in PPARα–/– mice. In contrast, iloprost induces a robust angiogenic response in wild-type mice, along with local upregulation of VEGF. Importantly, mice lacking the PPARα gene exhibit a normal angiogenic response to VEGF, indicating that the absence of PPARα does not result in a general impairment of angiogenesis, but specifically affects the ability of iloprost to induce angiogenesis. Our data demonstrate unexpected functional relationships between the PGI2 system and the PPAR signaling pathway and shed new light on the molecular mechanisms involved in iloprost-induced angiogenesis.

Keywords:
Iloprost, Prostacyclin, Peroxisome proliferator-activated receptor-α, Angiogenesis, Vascular endothelial growth factor
1.
Hsu HH, Rubin LJ: Iloprost inhalation solution for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother 2005;6:1921–1930.
2.
Pope J, Fenlon D, Thompson A, Shea B, Furst D, Wells G, et al: Iloprost and cisaprost for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2000;2:CD000953.
3.
Poggesi L, Comeglio M: The role of iloprost in the treatment of critical ischemia of the limbs (in Italian). Ann Ital Med Int 1993;8(suppl):71S–77S.
4.
Pola R, Gaetani E, Flex A, Aprahamian TR, Bosch-Marce M, Losordo DW, et al: Comparative analysis of the in vivo angiogenic properties of stable prostacyclin analogs: a possible role for peroxisome proliferator-activated receptors. J Mol Cell Cardiol 2004;36:363–370.
5.
Namba T, Oida H, Sugimoto Y, Kakizuka A, Negishi M, Ichikawa A, et al: cDNA cloning of a mouse prostacyclin receptor. Multiple signaling pathways and expression in thymic medulla. J Biol Chem 1994;269:9986–9992.
6.
Hertz R, Berman I, Keppler D, Bar-Tana J: Activation of gene transcription by prostacyclin analogues is mediated by the peroxisome-proliferators-activated receptor (PPAR). Eur J Biochem 1996;235:242–247.
7.
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, et al: The nuclear receptor superfamily: the second decade. Cell 1995;83:835–839.
8.
Zhao Q, Egashira K, Inoue S, Usui M, Kitamoto S, Ni W, et al: Vascular endothelial growth factor is necessary in the development of arteriosclerosis by recruiting/activating monocytes in a rat model of long-term inhibition of nitric oxide synthesis. Circulation 2002;105:1110–1115.
9.
Zachary I, Gliki G: Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res 2001;49:568–581.
10.
Gately S, Lee WW: Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 2004;31(2 suppl 7):2–11.
11.
Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin J, Gonzalez FJ, et al: A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice. J Clin Invest 1998;102:1083–1091.
12.
Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, et al: Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 1995;15:3012–3022.
13.
Schmuth M, Schoonjans K, Yu QC, Fluhr JW, Crumrine D, Hachem JP, et al: Role of peroxisome proliferator-activated receptor alpha in epidermal development in utero. J Invest Dermatol 2002;119:1298–1303.
14.
van Albada ME, Berger RM, Niggebrugge M, van Veghel R, Cromme-Dijkhuis AH, Schoemaker RG: Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertension. Eur J Pharmacol 2006;549:107–116.
15.
Pyrpasopoulou A, Aslanidis S: Clinical images: iloprost-induced vascular remodeling. Arthritis Rheum 2007;56:2243.
16.
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC: Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088–2093.
17.
Opitz CF, Wensel R, Winkler J, Halank M, Bruch L, Kleber FX, et al: Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J 2005;26:1895–1902.
© 2008 S. Karger AG, Basel
2008
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